One of the chief characteristics of the retinal capillary is the presence of a blood-retinal barrier (BRB), which prevents plasma proteins or toxic substances from reaching the retinal tissue. The BRB is due to two components: a zonular occludens which encircles adjacent endothelial cells and seal off the intercellular space and a paucity of endothelial vesicles which might otherwise transport proteins across the cell. A breakdown in the BRB occurs in many conditions affecting the retina and is due either to junctional opening or to enhanced transendothelial vesicular transport. In preliminary studies we have demonstrated that the outer retinal capillaries of RCS rats with inherited retinal degeneration become permeable to intravenously injected small proteins such as microperoxidase (MP) and horseradish peroxidase (HRP). Leakage of these proteins is due to enhanced transendothelial vesicular transport. The proposed experiments will examine the influence of molecular weight, size and charge on permeability. The role of anionic (negative) sites, the chemical composition of these sites and the role of lectin receptors in the endothelial surface will also be studied. Because of evidence that endothelial cell lysosomes may be part of the BRB, the fusion of protein-filled endothelial vesicles and lysosomes will be examined. Also included, are studies of retinal arteriole permeability to proteins and the endocytic capabilities of retinal capillary and arteriolar pericytes. Pericytes may serve as a last line of defense against proteins that breach the vessel wall. Attempts will also be made to stimulate vesicle uptake of proteins by the capillary endothelium. Lastly, the inherited retinal degeneration in C3H mice will be studied using the tracer techniques employed for the RCS rat. These experiments are aimed at determining whether retinal capillary leakage by the vesicular pathway occurs in other conditions in which there is extensive degeneration of the photoreceptor cells. The proposed studies should provide new information on the mechanisms involved in retinal capillary permeability. The data obtained may provide a basis for therapy aimed at controlling or preventing capillary leakage.